The alpha1beta1 integrin (termed very late antigen-1, VLA-1) is a heterodimeric collagen receptor that becomes expressed only on primed CD45RO+ T cells and in particular on T-cells infiltrating inflamed tissues. Thus, for example, in rheumatoid arthritis (RA) patients, a large fraction of the CD4+ T cells infiltrating the inflamed synovium express VLA-1. In addition, other activated immune cells (excluding B cells) and various mesenchymal and endothelial cells express VLA-1. Recent studies in animal models of inflammation demonstrated the critical role of VLA-1 in certain immune mediated responses. Importantly, although these studies suggest a therapeutic potential for VLA-1 blockade in inflammation, the exact mechanisms involved have not been well studied. The main theme of this proposal is to study aspects of VLA- 1 biology that are unique to subsets of effector T cells. Our preliminary studies address novel aspects of VLA- 1 biology in CD4+ T cells, the subset that orchestrates most cognate immune responses. We find that VLA-1 expression in vivo is associated with T helper (TH)1 polarization. Furthermore, activating fresh unselected PBL ex vivo in the presence of TH1 (versus TH2) polarizing cytokines increases the fraction of VLA-1+ cells. In addition, following polyclonal activation by anti-CD3 mAbs, super-antigens, or the mixed leukocyte reaction (MLR), VLA- 1 expression is restricted only to a relatively small subset of the activated CD4+CD45RO+ cells, and lines and clones with a stable VLA-1- or VLA-1 + phenotype can be generated. In contrast re-activated memory-antigen-primed (e.g., by tetanus toxoid) CD4+ CD45RO+ T cells were highly enriched for the VLA-1+ phenotype. We therefore hypothesize that VLA-1 expression within the effector and memory CD4+ T cell population represents a functionally relevant lineage commitment. In this regard, it has already been shown that VLA-1 mediates adhesion and migration of T cells in collagenous matrices, while simultaneously inducing distinct signaling pathways that support cell cycle progression and cytokine secretion. Our specific aims are: (1) To further characterize the VLA-1 + and VLA-1- subsets with respect to: (a) co-expression patterns of additional functionally relevant markers, (b) effector functions, including: cytokine secretion, and helper, suppressor or cytotoxic capacity; (2) To further study in human autoimmunity, if the VLA-1 + phenotype is associated with functional auto-aggressive CD4+ TH1 cells and can serve as a marker to identify clonal expansions of pathogenic T cells; (3) To determine the effect of VLA-1 blockade in vivo on CD4+ TH1 cell effector functions in humans. (4) To study the effects of anti-VLA-1 immuno-therapy on functionally relevant auto-aggressive CD4+ TH1 in vivo in mouse models of experimental allergic encephalomyelitis (EAE).